PMID- 36254341
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221019
IS  - 2045-7022 (Print)
IS  - 2045-7022 (Electronic)
IS  - 2045-7022 (Linking)
VI  - 12
IP  - 10
DP  - 2022 Oct
TI  - Determining biomarkers for evaluation and diagnosis of hereditary angioedema.
PG  - e12202
LID - 10.1002/clt2.12202 [doi]
LID - e12202
AB  - RATIONALE: Kallikrein-bradykinin-forming cascade is known to cause hereditary 
      angioedema (HAE) acute angioedema (AE) attacks. Further research of HAE attacks 
      is needed to explain disease heterogeneity, predict treatment response and 
      identify biomarkers for monitoring HAE attacks. Differential expression of the 
      microvascular endothelial cell-surface receptors for example, g-C1qR, 
      cytokeratin-1, and plasminogen-activator-urokinase-receptor (PLAUR) were 
      hypothesized as biomarkers of AE attacks. METHOD: To understand HAE attacks, the 
      differentially expressed genes (DEGs) in RNAseq and mi-RNAseq data of total RNA 
      extracted from skin biopsies of lesional versus non-lesional skin collected 
      during and between attacks in Type-1 HAE patients (n = 11; F:M = 8:3) were 
      compared. To understand the HAE variants, DEGs in skin biopsies from HAE with 
      normal C1 inhibitor (n = 5, F:M = 5:0), and non-HAE (n = 7; F:M = 3:4) patients 
      were compared. Gene-set enrichment analyses and regulator effects analysis of 
      these DEGs identified biological pathways in HAE attacks and their regulators. 
      RESULTS: PLAUR gene, encoding urokinase-type plasminogen activator (u-PAR), was 
      constitutively over-expressed in HAE-Type-1 versus non-HAE controls suggestive of 
      overactive u-PAR-mediated signaling via binding to Factor-XII. Baseline PLAUR 
      expression was associated with severe AE (p = 0.05). The 18 significant DEGs 
      investigated between baseline and AE attack samples in Type1-HAE were enriched in 
      beta1/beta3-integrin cell surface interactions and IL-6-mediated signaling. 
      Regulator effects analysis suggests a role for IL-1b in HAE flares. AKT2, the 
      mRNA regulated by the differentially-expressed miR-184A, was also associated with 
      HAE attacks. CONCLUSION: Angiopoetin-activated beta1-integrin signaling pathways 
      causing endothelial destabilization, and avid binding of factor XII to u-PAR are 
      possible novel mechanisms for progression of the endothelial 
      kinin-bradykinin-forming cascade in HAE attacks.
CI  - (c) 2022 The Authors. Clinical and Translational Allergy published by John Wiley & 
      Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.
FAU - Singh, Umesh
AU  - Singh U
AUID- ORCID: 0000-0003-1830-6262
AD  - University of Cincinnati College of Medicine Cincinnati Ohio USA.
FAU - Bernstein, Jonathan A
AU  - Bernstein JA
AD  - University of Cincinnati College of Medicine Cincinnati Ohio USA.
LA  - eng
PT  - Journal Article
DEP - 20221012
PL  - England
TA  - Clin Transl Allergy
JT  - Clinical and translational allergy
JID - 101576043
PMC - PMC9557132
OTO - NOTNLM
OT  - HAE attacks
OT  - HAE with normal C1 inhibitor
OT  - IL-1b, beta1/beta3-integrin
OT  - IL-6
OT  - PLAUR gene
OT  - RNAseq
OT  - biomarkers
OT  - differentially expressed genes
OT  - hereditary angioedema
OT  - heterogeneity
OT  - immunology
OT  - immunotherapy
OT  - kallikrein-bradykinin
OT  - other
COIS- Umesh Singh: Nothing to disclose. Jonathan A. Bernstein: PI, consultant, speaker: 
      Takeda/Shire, CSL Behring, Pharming, Biocyrst; PI, consultant: Biomarin, 
      Kalvista, Ionis; Consultant:; Pharvaris, Astria.
EDAT- 2022/10/19 06:00
MHDA- 2022/10/19 06:01
PMCR- 2022/10/12
CRDT- 2022/10/18 01:51
PHST- 2022/04/05 00:00 [received]
PHST- 2022/07/31 00:00 [revised]
PHST- 2022/08/16 00:00 [accepted]
PHST- 2022/10/18 01:51 [entrez]
PHST- 2022/10/19 06:00 [pubmed]
PHST- 2022/10/19 06:01 [medline]
PHST- 2022/10/12 00:00 [pmc-release]
AID - CLT212202 [pii]
AID - 10.1002/clt2.12202 [doi]
PST - epublish
SO  - Clin Transl Allergy. 2022 Oct 12;12(10):e12202. doi: 10.1002/clt2.12202. 
      eCollection 2022 Oct.